This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

The treatment of schizophrenia with multiple antipsychotic drugs is common, but the benefits and risks are not known. In a randomized, double-blind study, we evaluated patients with schizophrenia and a poor response to treatment with clozapine. The patients continued to take clozapine and were randomly assigned to receive eight weeks of daily augmentation with 3 mg of risperidone or with placebo. This course of treatment was followed by an optional 18 weeks of augmentation with risperidone. The primary outcome was reduction in the total score for severity of symptoms on the Positive and Negative Syndrome Scale (PANSS). The secondary outcomes included cognitive functioning. A total of 68 patients were randomly assigned to treatment. In the double-blind phase, the mean total score for the severity of symptoms decreased from baseline to eight weeks in both the risperidone and the placebo groups. There was no statistically significant difference in symptomatic benefit between augmentation with risperidone and placebo: 9 of 34 patients receiving placebo and 6 of 34 receiving risperidone responded to treatment (P=0.38). The mean difference in the change in PANSS scores from baseline to eight weeks between those receiving risperidone and those receiving placebo was 0.1 (95 percent confidence interval, −7.3 to 7.0). The verbal working-memory index showed a small decline in the risperidone group and a small improvement in the placebo group (P=0.02 for the comparison between the two groups in the change from baseline). The increase in fasting blood glucose levels was mildly greater in the risperidone group than in the placebo group (16.2 vs. 1.8 mg per deciliter [0.90 vs. 0.10 mmol per liter], P=0.04). The incidence and severity of other side effects did not differ between the two groups. In this short-term study, the addition of risperidone to clozapine did not improve symptoms in patients with severe schizophrenia. (ClinicalTrials.gov number, NCT00272584)

The present study aimed (1) to determine the proportion of patients treated with persistent antipsychotic polypharmacy in an outpatient population and (2) to determine if persistent antipsychotic polypharmacy is associated with excessive dosing. Using a province-wide network that links all pharmacies in British Columbia, Canada, to a central set of data systems, we identified community mental health outpatients who had been treated with the same pharmacologic regimen for at least 90 days. Apart from antipsychotics, data collection included anticholinergics, antidepressants, mood stabilizers, benzodiazepines, lipid-lowering agents, and antidiabetic agents. Demographic data including sex, age, and diagnosis were obtained from the patient's chart. In order to compare dosages of the various antipsychotics we used a fixed unit of measurement based on dividing the prescribed daily dose (PDD) by the defined daily dose (DDD). A PDD/DDD ratio greater than 1.5 was defined as excessive dosing. Four hundred thirty-five patients met the inclusion criteria and were included in the analysis. Overall, the prevalence of persistent antipsychotic polypharmacy was 25.7% for the entire cohort. The prevalence of persistent antipsychotic polypharmacy was highest for patients with schizoaffective disorder (33.7%), followed by schizophrenia (31.7%), psychosis not otherwise specified (20.0%), bipolar disorder (16.9%), and major depression (14.3%). The mean +/- SD PDD/DDD ratio for all patients prescribed persistent antipsychotic polypharmacy was not only excessive, it was significantly greater compared to that of patients receiving antipsychotic monotherapy (1.94 +/- 0.12 vs 0.94 +/- 0.04, P < .005). Using a diagnostically heterogeneous outpatient population, this study is, we believe, the first to report that persistent antipsychotic polypharmacy is associated with excessive dosing, in and of itself as well as compared to antipsychotic monotherapy.

Objective: To perform a retrospective survey of discharge medications at a tertiary care psychiatric facility and to assess the incidence of antipsychotic polypharmacy. Method: This is a retrospective survey that used the Department of Pharmacy's computer database to obtain relevant discharge information on all nongeriatric patients with schizophrenia discharged from Riverview Hospital between November 1, 1996 and October 31, 1998. From a total of 492 eligible patients, 229 met the inclusion criteria and formed the database for the survey. Results: The main finding of the survey was that 27.5% of our discharged patients diagnosed with schizophrenia left our facility on an antipsychotic polypharmacy regimen. Compared with patients discharged on a single antipsychotic, the pooled data revealed a significantly greater use of anticholinergic agents in those patients prescribed an antipsychotic polypharmacy regimen. Further, of the atypical agents, only risperidone showed a statistically significant reduction in dosage when coprescribed with a second antipsychotic. Conclusion: Although antipsychotic polypharmacy persists today, as it has over the past 30 years, evidence-based data to support this controversial treatment strategy is lacking. As a result clinicians are relying on their clinical experience, and perhaps intuition, to design antipsychotic polypharmacy treatment protocols. Efforts should be made to replace subjective clinical impression with a more rational approach to antipsychotic polypharmacy—one that is based on pharmacodynamic and pharmacokinetic understanding of drug action.